The mammalian olfactory system displays remarkable sensitivity and specificity in the detection of odorant molecules. G protein-coupled receptors present in the cilia of the olfactory neurons activate a transduction cascade leading to electrical activity and the propagation of sensory information to the brain. The discovery of a large family of olfactory receptor (OR) genes nearly a decade ago provided an explanation for the differential sensitivity of individual olfactory neurons. Moreover, the apparent expression of only a single receptor type in each cell suggests that the selectivity and specificity characteristic of each neuron reflects the functional properties of the underlying receptor protein. However, until recently it had not been possible to characterize OR function by expression in heterologous systems. Preliminary analysis of a few receptors indicates that they may display relatively narrow ligand specificity. The development of functional expression systems presents an important opportunity to define the molecular mechanism underlying odorant recognition. Interestingly, the threshold for detection of some odorants differs greatly among individuals in the population. These specific anosmias and hyposmias appear to have a genetic basis and may derive from unappreciated variations in the complement and functionality of individual receptors. We propose to define the molecular logic used by odorant receptors to bind and discriminate among structurally related ligands. These experiments will characterize the ligand specificity of a large number of mouse olfactory receptors and probe key residues in the ligand recognition pocket. The evolution and structural conservation of olfactory receptors make them uniquely amenable to a systematic dissection of molecular recognition. We will utilize molecular and functional approaches to elucidate the genetic and genomic variations that lead to specific anosmias. These experiments will complement those derived from in vitro analysis by providing information on receptor genes that are functionally important in the behavioral response of an animal. These experiments will afford new insights into the basis of odorant discrimination, information coding and the genetic basis of variation in sensory perception by the mammalian brain.